Existence of Length-Dependent Modulation of Cross-Bridge Cycling Kinetics in Right Ventricles of Non-Failing and Failing Human Myocardium

Heart failure affects more than 5 million patients in the United States. The mechanisms by which the heart regulates cross-bridge cycling rate and if and how such regulation is altered in heart failure are poorly understood. One possible modulator of this cycling rate is muscle length. In a previously published study, we showed that the rate of tension redevelopment (ktr) can be reproducibly measured in intact cardiac trabeculae using a novel approach. Furthermore, we showed that slacking trabeculae from Lopt corresponding to end-diastolic volume in vivo) to L90 (corresponding to end-systolic volume in vivo) increases ktr by about 60%. While this regulation is present in a small animal model, its role in human myocardium in both health and disease remains unanswered. Therefore, we extended our studies using our novel method to right ventricular trabeculae isolated from non-failing donor and patients with heart failure. The failing samples had preserved length-tension relationship, reduced force-frequency relationship, and β-adrenergic desensitization as compared to non-failing donors. Contractile and relaxation kinetics of twitch of both non-failing and failing trabeculae were slowed down with increasing muscle length from L90 to Lopt. We were able to reproducibly measure ktr in intact human cardiac trabeculae; ktr during maximal myofilament activation in both non-failing and failing samples decreased with increasing muscle length. This effect of muscle length on ktr was also present at sub-maximal activation. These effects can be potentially due to post-translational modifications. We have preliminary ktr data after rapid length changes during maximal activation and PKA/PKCBII inhibition at maximal and sub-maximal activation levels. The overall data provides evidence that muscle length can regulate cross-bridge cycling kinetics in both non-failing and failing human hearts.